Deregulation of Akt/Protein Kinase B (PKB) is implicated in the pathogenesis of many disorders including cancer and diabetes. Akt/PKB activation requires the phosphorylation of threonine 308 in the activation loop by the phosphoinositide-dependent kinase 1 (PDK1) and serine 473 within the C-terminal hydrophobic motif by an unknown kinase.
The Akt/PKB kinase is a well-characterized effector of phosphoinositide 3-kinase (PI3K) and its deregulation plays important roles in the pathogenesis of human cancers. PI3K is necessary for the activation of Akt/PKB and current models suggest that phosphatidylinositol-3,4,5-triphosphates produced upon growth factor stimulation recruit Akt/PKB to the plasma membrane by binding to its N-terminal pleckstrin homology (PH) domain. At the membrane Akt/PKB is phosphorylated on two key residues: threonine 308 of the activation loop by PDK1 (D. R. Alessi et al., Curr Biol 7, 261 (1997); L. Stephens et al., Science 279, 710 (1998)), and serine 473 in the hydrophobic motif of the C-terminal tail by a kinase whose identity has been elusive. The role of S473 phosphorylation is controversial, but there is an emerging view that it precedes the phosphorylation of T308 and is important for the recognition and activation of Akt/PKB by PDK1 (M. P. Scheid et al., Mol Cell Biol 22, 6247 (2002); J. Yang et al., Mol Cell 9, 1227 (2002); D. R. Alessi et al., Embo J 15, 6541 (1996)).